ABSTRACT The role of the complex interplay of the nasopharyngeal microbiome, including the virome, and the systemic or local immune response in predicting complications from respiratory viral infections (RVIs) and their outcomes in immunocompromised patients, remains unknown and needs to be determined. The long-term goal is to iden- tify host immunologic factors and respiratory microbiome changes during RVIs that are associated with poor outcome, mainly lower respiratory tract infection (LRTI), death, or pulmonary impairment (PI) in hematopoietic cell transplant (HCT) recipients, and in patients with leukemia or lung cancer. The overall objective of this pro- posal is to identify host and pathogen factors as predictors of poor outcome in a high-risk population of cancer patients with RVIs. Based on preliminary findings, our central hypothesis is that dysbiosis between respiratory viruses and the microbiome, in conjunction with specific immune response elements, could act as a trigger or cofactor for poor outcome in RVIs. Building on the investigators? expertise, the study hypothesis will be tested through the following two specific aims. Aim 1: To determine whether serial changes in the respiratory microbi- ome/virome resulting from RVIs affect the risk of progression to LRTI, death, and PI in HCT recipients and in patients with leukemia or lung cancer. Sub-aim 1.1: To identify novel or undiagnosed viruses in HCT recipients with respiratory symptoms but negative routine molecular viral diagnostic tests. Sub-aim 1.2: To characterize variations in the microbiome/virome based on geography (US and Brazil) after RVIs in HCT recipients and in patients with leukemia or lung cancer. Aim 2: To define serial systemic and local immune responses after RVIs in HCT recipients and in patients with leukemia or lung cancer to determine whether an association exists be- tween immune profiles and progression to LRTI, death, and PI. The research design will be a prospective mul- tisite cohort study between two sister institutions, The Univ. of Texas MD Anderson Cancer Center in Texas, US, and the A.C. Camargo Cancer Center in Sao Paulo, Brazil. Methods: Nasopharyngeal microbiota profiles of patients with RVIs will be achieved by next-generation sequencing (NGS). In parallel, RVI-induced host im- mune responses will be investigated using high parameter flow cytometry of cellular immune profiles (periph- eral blood), as well as multiplex analyte detection of immune mediators using a bead detection platform (blood and nasal wash). The contribution of the proposed research will provide a comprehensive understanding of risk factors, including the interplay of microbiome changes and host immune responses, for progression to poor outcome after RVIs in a high-risk population. This application is innovative as it represents a new and substan- tive departure from the status quo by shifting focus from epidemiological studies to metagenomics NGS and to generation of high dimensional local and systemic immune profiles, on outcome in RVIs in this vulnerable pop- ulation. This original approach will lead to broader understanding of pathogenesis and to better diagnostic tools and treatment strategies to improve outcome in immunocompromised patients